Peptides Having For Example Antiangiogenic Activity and Applications Thereof In Therapeutics

• US 20080171697A1
• Filed: 09/24/2004
• Published: 07/17/2008
• Est. Priority Date: 09/25/2003
• Status: Abandoned Application

• Current Assignee: Theraptosis S.A.
• Original Assignee: Theraptosis S.A.
• Inventors: Dupont, Sylvie, Jacotot, Etienne, Borgne-Sanchez, Annie, Rebouillat, Dominique
• Application Number:
  US10/573,576
• Publication Number:
  US 20080171697A1
• Time in Patent Office: Days
• US Class Current: 514/9
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/001 by chemical synthesis
• CPC Class Codes: C07K 14/78 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]

Abstract

The invention relates to cyclised peptides corresponding to sequence SEQ ID N^o1: X₁X₂RGDX₃FGX₄X₅LLFIHFX₆IGSX₇HSX₈IX₉, wherein: the letters without any numerical index correspond to amino acids defined by the single-letter international code; X₁ is G or GG having an amino-terminal end which may or may not be free; X₂ is either a C, in which case X₂=X₄, the two Cs being connected by a disulphide bridge, or X₂ is capable of forming a lactam bridge with X₄, either X₂ or X₄ being an amino acid bearing an acid group, such as A or D, and the other bearing an amino function such as Q, N; X₃ is either an M pattern or a norleucine pattern; X₅ is one or several di-, tri-, or tetra-peptide patterns comprising G or a combination of G and S, or X₅ is a C pattern having a side-chain which serves as a covalent linkage point with a 3-nitro-2-pyridinesulphenyl group which is located at the N-terminal end of the next amino acid (L); X₆ is either an R pattern or a K pattern; X₇ is either an R pattern or a K pattern; X₈ is either an R pattern or a K pattern; and X₉ is an aliphatic amino acid (such as G or A) having an amide C-terminal end. The inventive peptides can be used as active ingredients in medicaments, for example, for the treatment of pathologies linked to hypervascularisation.

Claims

1. A peptide having, in particular, an antiangiogenic activity, characterized in that it is a cyclized peptide corresponding to the sequence

SEQ ID No 1:

X₁X₂RGDX₃FGX₄X₅LLFIHFX₆IGSX₇HSX₈IX₉ in which;

the letters without any numerical index correspond to amino acids defined by the single-letter international code,

X₁ is either a G or a GG, the amino-terminal end of which is free, alkylated, acylated, or in particular acetylated, or contains a labeling group, such as the biotinyl group,

X₂ is either a C, in which case X₂=X₄, the two Cs then being connected by a disulfide bridge, or X₂ is capable of forming a lactam bridge with X₄, one of X₂ or X₄ being an amino acid bearing an acid group, such as A or D, the other bearing an amino function, such as Q or N,

X₃ is either an M motif or a norleucine motif,

X₅ is either a motif, or a succession of two di-, tri- or tetrapeptide motifs composed of G or a combination of G and of S, such as GG, GGG, GGGG, GGS, GGGS or GGSGGS, or else X₅ is a C motif, the side chain (thiol function) of which serves as a point for covalent bonding with a 3-nitro-2-pyridinesulfenyl group located on the N-terminal end of the next amino acid (L),

X₆ is either an R motif or a K motif,

X₇ is either an R motif or a K motif,

X₈ is either an R motif or a K motif,

X₉ is an aliphatic amino acid (such as G or A), the C-terminal end of which is amidated.

2. The peptide as claimed in claim 1, characterized in that it corresponds to the sequence

SEQ ID No 2:

GG*CRGDMFG*CGGLLFIHFRIGSRHSRIG (*indicates a disulfide bridge connecting the two C motifs).

3. The peptide as claimed in claim 1, characterized in that it is modified compared with the native peptide and has, in particular, an alkylated group at its N-terminal end, and/or in that more amino acids are replaced with one or its/their dextrorotary form (_Daa), and/or in that it contains one or more peptide bonds so as to form bioisosters, for example the reduction of an amide bridge to —

CH₂NH—

, or a retro-inverso reaction.

4. The peptide as claimed in claim 2, in which the RGD motif is exposed via a disulfide bridge between two cysteines, in particular the peptides of sequences SEQ ID No 3 to 10:

5. The peptide as claimed in claim 1, characterized in that it contains a sequence

6. The peptide as claimed in claim 5, characterized in that it corresponds to the sequences SEQ ID No 12 to SEQ ID No 23:

7. The peptide as claimed in claim 1, characterized in that it induces apoptosis in human endothelial cells expressing α

Vβ

3 receptors.

8. The peptide as claimed in claim 1, characterized in that it undergoes endocytosis by human endothelial cells expressing α

Vβ

3 receptors, localizes in the mitochondrial compartment, and exerts a mitochondriotoxic effect.

9. A pharmaceutical composition, characterized in that it contains a therapeutically effective amount of at least one peptide as defined in claim 1, in combination with a pharmaceutically acceptable vehicle.

10. The pharmaceutical composition as claimed in claim 9, characterized in that it is in the pharmaceutical form suitable for its administration by injection, in particular in the form of an injectable solution for intravenous administration.

11. The use of peptides as claimed in claim 1, for producing antiangiogenic medicaments for the treatment of pathologies due to hypervascularization.

12. The use as claimed in claim 11, for producing medicaments for the treatment of solid tumors such as pulmonary tumors, adenomas, melanomas, prostate cancer, breast cancer, colon cancer, pancreatic cancer or osteosarcomas, or the treatment of diabetic retinopathies and of arthritis.